Forms Of Von Willebrand Disease Research Articles

Novel cysteine substitution p.(Cys1084Tyr) causes variable expressivity of qualitative and quantitative VWF defects

Abstractvon Willebrand factor (VWF) is an extremely cysteine-rich multimeric protein that is essential for maintaining normal hemostasis. The cysteine residues of VWF monomers form intra- and intermolecular disulfide bonds that regulate its structural conformation, multimer distribution, and ultimately its hemostatic activity. In this study, we investigated and characterized the molecular and pathogenic mechanisms through which a novel cysteine variant p.(Cys1084Tyr) causes an unusual, mixed phenotype form of von Willebrand disease (VWD). Phenotypic data including bleeding scores, laboratory values, VWF multimer distribution, and desmopressin response kinetics were investigated in 5 members (2 parents and 3 daughters) of a consanguineous family. VWF synthesis and secretion were also assessed in a heterologous expression system and in a transient transgenic mouse model. Heterozygosity for p.(Cys1084Tyr) was associated with variable expressivity of qualitative VWF defects. Heterozygous individuals had reduced VWF:GPIbM (<0.40 IU/mL) and VWF:CB (<0.35 IU/mL), as well as relative reductions in high-molecular-weight multimers, consistent with type 2A VWD. In addition to these qualitative defects, homozygous individuals also displayed reduced factor VIII (FVIII):C/VWF:Ag, leading to very low FVIII levels (0.03-0.1 IU/mL) and reduced VWF:Ag (<0.40 IU/mL) and VWF:GPIbM (<0.30 IU/mL). Accelerated VWF clearance and impaired VWF secretion contributed to the fully expressed homozygous phenotype with impaired secretion arising because of disordered disulfide connectivity.

Acquired Von Willebrand Syndrome (AVWS) in cardiovascular disease: a state of the art review for clinicians.

Von Willebrand Factor (vWF) is a large glycoprotein with a broad range of physiological and pathological functions in health and disease. While vWF is critical for normal hemostasis, vascular integrity and repair, quantitative and qualitative abnormalities in the molecule can predispose to serious bleeding and thrombosis. The heritable form of von Willebrand Disease was first described nearly a century ago, but more recently, recognition of an acquired condition known as acquired von Willebrand Syndrome (AVWF) has emerged in persons with hematological, endocrine and cardiovascular diseases, disorders and conditions. An in-depth understanding of the causes, diagnostic approach and management of AVWS is important for practicing clinicians.

Rare forms of von Willebrand disease.

von Willebrand disease (VWD) arises from deficiency and/or defect(s) of plasma von Willebrand factor (VWF). In turn, plasma VWF is an adhesive protein which primarily functions by anchoring platelets to regions of vascular injury, thereby assisting prevention of bleeding. There is a proportional reduction also in Factor VIII, due to the absence of the stabilizing and anti-proteolytic effect that VWF normally exerts. VWD is reportedly the most common inherited bleeding disorder and can be classified into quantitative and qualitative defects, with type 1 and 3 VWD respectively identifying partial and total quantitative deficiency of VWF, and type 2 VWD identifying qualitative defects of VWF. The relative incidence of each subtype of VWD differs according to the locality and the ability of clinicians and laboratories to correctly diagnose and classify cases. In general, type 1 VWD is considered the most common type of VWD, whereas types 2 and 3 represent rarer forms. However, in developing countries, and partly because of consanguinity, type 3 VWD is over-represented. This review primarily focuses on the rarer forms of VWD, which typically comprise types 2 (A, B, M and N) and 3 VWD. The review also mentions type 1 VWD, largely for completeness and comparability, and since purportedly "severe" type 1 VWD, albeit not a formally recognized subtype of type 1 VWD, would represent a relatively "rare" form of VWD.

Mutation G1629E Increases von Willebrand Factor Cleavage via a Cooperative Destabilization Mechanism

The large multimeric glycoprotein von Willebrand Factor (VWF) plays a pivotal adhesive role during primary hemostasis. VWF is cleaved by the protease ADAMTS13 as a down-regulatory mechanism to prevent excessive VWF-mediated platelet aggregation. For each VWF monomer, the ADAMTS13 cleavage site is located deeply buried inside the VWF A2 domain. External forces in vivo or denaturants in vitro trigger the unfolding of this domain, thereby leaving the cleavage site solvent-exposed and ready for cleavage. Mutations in the VWF A2 domain, facilitating the cleavage process, cause a distinct form of von Willebrand disease (VWD), VWD type 2A. In particular, the VWD type 2A Gly1629Glu mutation drastically accelerates the proteolytic cleavage activity, even in the absence of forces or denaturants. However, the effect of this mutation has not yet been quantified, in terms of kinetics or thermodynamics, nor has the underlying molecular mechanism been revealed. In this study, we addressed these questions by using fluorescence correlation spectroscopy, molecular dynamics simulations, and free energy calculations. The measured enzyme kinetics revealed a 20-fold increase in the cleavage rate for the Gly1629Glu mutant compared with the wild-type VWF. Cleavage was found cooperative with a cooperativity coefficient n = 2.3, suggesting that the mutant VWF gives access to multiple cleavage sites of the VWF multimer at the same time. According to our simulations and free energy calculations, the Gly1629Glu mutation causes structural perturbation in the A2 domain and thereby destabilizes the domain by ∼10 kJ/mol, promoting its unfolding. Taken together, the enhanced proteolytic activity of Gly1629Glu can be readily explained by an increased availability of the ADAMTS13 cleavage site through A2-domain-fold thermodynamic destabilization. Our study puts forward the Gly1629Glu mutant as a very efficient enzyme substrate for ADAMTS13 activity assays.

Human von Willebrand factor/factor VIII concentrates in the management of pediatric patients with von Willebrand disease/hemophilia A.

Several plasma-derived intermediate and high-purity concentrates containing von Willebrand factor (VWF) and factor VIII (FVIII) are currently available. The main role of these products in the management of the pediatric population is represented by the replacement therapy in patients with severe or intermediate forms of von Willebrand disease, in whom other treatments are ineffective or contraindicated. Another important role of VWF/FVIII concentrates in children may be their use in immune tolerance induction (ITI) protocols. ITI is particularly recommended for hemophilia A children who have developed an inhibitor against FVIII, currently the most serious complication of substitutive treatment in hemophilia. Although recombinant concentrates may represent the preferred option in children with hemophilia A, VWF/FVIII concentrates may offer an advantage in rescuing patients who failed previous ITI.

Baseline factor VIII plasma levels and age at first bleeding in patients with severe forms of von Willebrand disease.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The age of bleeding onset is highly variable, also in patients with similar degree of severity. The primary aim of this study was to evaluate whether baseline factor VIII (FVIII) plasma levels correlate with age at first bleeding in patients with extremely low levels of VWF:RCo (<6 IU dL(-1) ). One hundred and three patients with VWF:RCo <6 IU dL(-1) (6 VWD1, 73 VWD2 and 24 VWD3) undergoing a medical examination between September 2010 and September 2013 were included. The relationship between baseline FVIII levels and age at first bleeding was tested in a multivariable linear regression model, adjusting for sex. The median age at first bleeding was lower in patients with VWD3 than in those with severe forms of VWD1 or VWD2 (1 year vs. 7 and 8 years, respectively, P < 0.0001). A positive non-linear relationship between FVIII levels and age at first bleeding was found, the latter increasing by 5 years for every 10 IU dL(-1) increase of FVIII (β = 4.95 [95% CI: 2.02-7.87]) until levels of 30 IU dL(-1) , after which the age increased slowly. This relationship was not found in VWD 2A and 2B. In 65 patients (63%) there was a more than 6-month delay between bleeding onset and VWD diagnosis, with no difference over decades. Baseline FVIII plasma levels influence the age at bleeding onset in VWD patients with extremely low levels of VWF:RCo, except in those with types 2A and 2B.

Heydeʼs Syndrome: A Large Retrospective Evaluation of the Link Between Angioectatic Bleeding and Aortic Stenosis

Introduction: The association between aortic stenosis (AS) and gastrointestinal (GI) bleeding has been studied extensively. Heyde's syndrome earmarks intestinal angioectasia as the source of bleeding. The mechanism underlying this pathophysiology is an acquired form of von Willebrand disease, in which there is a deficiency of large multimers of von Willebrand factor as the result of unregulated cleavage in the setting of increased shear stress across a stenotic aortic valve. The subsequent decline in hemostatic competence is thought to lead to the development of angioectasia. In spite of the significant advances in describing this pathophysiologic mechanism, controversy over the prevalence of the association continues. This study retrospectively explored the prevalence and severity of AS in patients with endoscopically proven angioectasia. Methods: We identified all patients between 2012-2014 who were found to have angioectasia as demonstrated by GI endoscopy (including EGD, colonoscopy, deep bowel enteroscopy and video capsule endoscopy) and who had an echocardiogram. The prevalence of AS was evaluated, and those noted to have AS were stratified with regards to severity on the basis of transvalvular gradients. Results: We found 238 patients with endoscopically proven GI angioectasia and who had echocardiograms. Patients who had undergone remote aortic valve replacements (AVR) who had normally functioning prosthetic valves during the study period were excluded, as the presence of angioectasia prior to AVR could not be objectively demonstrated. Of the 234 eligible subjects, 54 (23.1%) were found to have AS of any severity (p < 0.0001 assuming a prevalence of 10% of AS in the general population on the basis of current, age-controlled epidemiologic data). Analyzed in the context of severity based on transvalvular gradients, 23 were categorized as having mild stenosis, 20 as moderate stenosis and 11 as severe stenosis. Conclusion: This study represents the largest retrospective exploration of the link between GI angioectasia and AS using objective data. Our study demonstrated a 23% prevalence of AS in the studied population of patients with endoscopically proven angioectasia. This association was statistically significant and markedly greater than the highest estimates of AS in the general population in current literature. The prevalence of the association may justify screening patients with angioectasia for AS, given that AVR may mitigate morbidity and mortality associated with GI bleeding.

Severe, recessive type 1 is a discrete form of von Willebrand disease: the lesson learned from the c.1534-3C>A von Willebrand factor mutation

Type 1 von Willebrand disease (VWD) is transmitted mainly as a dominant trait - especially in forms involving von Willebrand factor (VWF) levels below 20 U/dL - and less frequently as a recessive trait. In the latter case, mutations at heterozygous level may be associated with type 3 carrier status, while mutations at homozygous or compound heterozygous level often coincide with type 3 VWD. Here we present a recessive, severe type 1 form as a distinct type of VWD.Eight patients with severe type 1 VWD belonging to 7 unrelated families were studied. They had VWF levels below 10 U/dL, FVIII higher than 10 U/dL, and a significantly lower than normal platelet VWF content. All patients were homozygous or compound heterozygous for the c.1534-3C>A VWF mutation, that simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription. This means that one of the three different mRNA generated assures the synthesis of normal VWF.The probands' relatives who were heterozygous for the c.1534-3C>A mutation always had low platelet VWF levels, sometimes with circulating VWF levels within normal range. This finding confirms the utility of measuring platelet VWF content to identify an abnormal VWF synthesis.Because the c.1534-3C>A mutation impairs, but does not abolish normal mRNA processing, it may never cause type 3 VWD. We propose a model of severe recessive type 1 VWF defect associated with mutations that sporadically go undetected by the cells’ molecular machinery, as the c.1534-3C>A VWF mutation. Bullet PointsWhat is known about this topic?- Type 1 VWD is transmitted mainly as a dominant trait.- Recessive type 1 mutations at homozygous or compound heterozygous level are often associated with type 3 VWD, and at heterozygous level with type 3 VWD carrier status.What does this paper add?- There are quantitative VWF mutations, such as c.1534-3C>A, that impair, but do not abolish normal mRNA processing.- The c.1534-3C>A VWF mutation simultaneously induces the skipping of exon 14, the activation of a cryptic splice site, and a normal VWF gene transcription.- The c.1534-3C>A mutation is the archetype of mutations that cause severe recessive type 1 VWD, but never type 3 VWD.- Recessive, severe type 1 appears to be a distinct form of VWD.

How I treat type 2 variant forms of von Willebrand disease

AbstractType 2 von Willebrand disease (VWD) includes a wide range of qualitative abnormalities of von Willebrand factor structure and function resulting in a variable bleeding tendency. According to the current classification, 4 different subtypes can be identified, each with distinctive phenotypic and therapeutic characteristics. Current available laboratory methods allow a straightforward approach to VWD subtyping, and although the precise molecular characterization remains complex, it is not required for appropriate treatment of the vast majority of cases. Desmopressin can be useful only in a few type 2 cases compared with patients with actual quantitative deficiency (type 1), most often in variants with a nearly normal multimeric pattern (type 2M). However, since no laboratory test accurately predicts response to desmopressin, a trial test should always be performed in all type 2 VWD patients, with the exception of type 2B ones. Replacement therapy with plasma-derived von Willebrand factor-factor VIII concentrates represents the safe mainstay of treatment of all patients, particularly those not responding to desmopressin or requiring a sustained hemostatic correction because of major surgery or bleeding. A significant patient bleeding history correlates with increased bleeding risk and should be considered in tailoring the optimal antihemorrhagic prophylaxis in the individual patient.

Successful aortic aneurysm repair in a woman with severe von Willebrand (type 3) disease.

von Willebrand disease type 3 (VWD3) is a rare but the most severe form of von Willebrand disease; it is due to almost complete lack of von Willebrand factor activity (VWF:RCo). It is inherited as autosomal recessive trait; whilst heterozygote carriers have mild, or no symptoms, patients with VWD3 show severe bleeding symptoms. In the laboratory, this is characterised by undetectable VWF:Ag, VWF:RCo, and reduced levels of factor VIII < 0.02 IU/dL. The bleeding is managed with von Willebrand/FVIII factor concentrate replacement therapy. In this rare but challenging case we report on the successful excision and repair of an ascending aortic aneurysm following adequate VWF/FVIII factor concentrate replacement using Haemate-P.

Acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder that mimics the inherited form of von Willebrand disease (VWD) in terms of laboratory findings and clinical presentation. To study the etiology of acquired VWD. The patients referred from various hospitals in and out of Mumbai were included in the study. Six patients with AVWS diagnosed at this center over the last 10 years were analyzed against 171 patients with inherited VWD. The differential diagnosis of AVWS was made based on reduced levels of von Willebrand antigen and von Willebrand ristocetin cofactor, decrease in ristocetin induced platelet aggregation, absence of correction in mixing studies with no prior history of bleeding problems and a negative family history for bleeding disorders. In three patients, the disease was associated with systematic lupus erythematosus, out of which one was also associated with Kikuchi lymphadenitis and second with autoimmune hemolytic anemia. Fourth case was associated with hypothyroidism and fifth was a case of dermatitis and vitiligo. The last patient was a case of hemophilia A with Burkitts lymphoma, who developed autoantibodies to von Willebrand factor. Except two patients, all other patients responded to immune suppressive therapy with corticosteroids, while the patient with hypothyroidism responded to oral thyroxine. AVWS is a rare condition and may often be missed or diagnosed as inherited disease associated with heterogeneous disease conditions.

Prophylaxis in bleeding disorders

Primary prophylaxis with coagulation factor concentrates has become the standard of care for children with hemophilia to reduce the risk of bleeding and related morbidity. However, several important questions remain unanswered regarding the optimal use of prophylaxis in patients with bleeding disorders. Limited data are available on the use of primary prophylaxis in adults with hemophilia, although tailoring the dose and schedule of prophylaxis in adults based on the clinical course of the disease may improve convenience and reduce costs without compromising efficacy. Patients with severe forms of von Willebrand disease (VWD) are at risk of serious bleeding episodes and may therefore benefit from prophylaxis; results from ongoing trials, such as the VWD International Prophylaxis (VIP) trial, are expected to provide more insight into the efficacy and safety of prophylaxis in these patients. For patients with other rare bleeding disorders, prophylaxis may be considered, depending on the clinical course of the disease and the availability of factor replacement therapy products; definitive recommendations, however, are not possible given the lack of comprehensive studies evaluating prophylaxis in this setting. Ongoing studies will help further define the role of coagulation factor concentrate prophylaxis in patients with bleeding disorders.

Clinical Efficacy and Safety Versus Biological Response of Desmopressin (DDAVP) In Inherited Von Willebrand Disease (VWD) Types 1 and 2: Initial Results From the International Study Group on DDAVP In VWD In a Cohort of 229 Patients

AbstractAbstract 238 Background:Desmopressin (DDAVP) is the treatment of choice for most patients with mild-moderate forms of von Willebrand Disease (VWD) because it can induce the release of von Willebrand Factor (VWF) from cellular compartments. However, despite the widespread use of DDAVP since 1977, there are only a few prospective clinical trials aimed at determining benefits and limits of this approach. Aims and design of the study:To correlate efficacy and safety with biological response of DDAVP in a large cohort of VWD1 and VWD2 patients followed-up for 24 months in a prospective observational study organized on behalf of the Working Party on DDAVP in VWD of the ISTH-SSC on VWF and of Italian Association of Hemophilia Centers (AICE). The study is registered at the EMEA with number EudraCT-2005-004496-38. Patients and Methods:VWD patients were enrolled after obtaining Ethical approval from local IRB. Inclusion criteria: inherited VWD without any age restriction, with previous diagnosis of VWD1 and VWD2 according to ISTH recommendations. Biological response: At enrollment patients were exposed to 0.3 ug/kg DDAVP intravenous injection and to blood withdrawal for measuring VWF/FVIII activities before and after 0.5, 1, 2 and 4 hours. Complete: both VWF:RCo and FVIII:C >50 IU/dL at 2 hours; partial: VWF:RCo or FVIII:C <50 IU/dL but increased at least 3-fold; absent: neither criterion. Clinical Response. Excellent: no excessive bleeding; Good: excess bleeding without need for VWF concentrate; Poor: excess bleeding with need for VWF concentrate. Statistical analyses were performed only on confirmed patients after the blind and independent evaluation by 2 members of the Steering Committee on these criteria: VWD=baseline levels of VWF:RCo <55 U/dL; VWD2= baseline VWF:RCo/Ag ratio≤ 0.6; VWD1 accelerated clearance: rapid increase of VWF:RCo/FVIII after 0.5–1 hrs with return to baseline levels after 2–4 hrs. Results:229/268 (85%) patients enrolled at 13 participating Centers in Argentina, Brazil, Canada, Germany, Italy and Hungary were found to meet the inclusion criteria. Demographic data and lab tests (mean+SD) at baseline were as follows:Parameters:Age(years)Gender(M/F)VWF:RCo(U/dL)VWF:Ag(U/dL)FVIII (U/dL)VWD1(n=198):32.7±16.772/12626.9±19.536.1±18.354.4±25.9VWD2 (n=31):40.4±17.916/1512±17.036.8±22.940.2±25.6Among VWD2, VWD2A(n=15), VWD2B(n=1), VWD2M(n=12), VWD2N(n=3) were identified. Biological response was complete, partial and absent in 89%, 10% and 1% of VWD and correlated with baseline levels of VWF:RCo<30 U/dL (Fisher's exact =0.001). Among VWD1, those (n=15) with C1130F and R1205H mutations showed accelerated clearance. During the 24-month follow-up, 62/86 (72%) patients received >1 injection of DDAVP for bleedings (n=102), deliveries (n=13), dental extractions (n=27), minor/major surgeries (n=46). Total number of injections was 652 with median, range/episode during bleedings (2,1-12), deliveries (3,1-3), dental extractions (1,1-6), surgeries (3.6,1-11). Clinical efficacy was excellent/good in bleedings (92%), deliveries (85%), dental extractions (100%), surgeries (91%). Poor efficacy was observed in 6 cases with VWD2A (n=4) during GI bleedings (n=3) or abdominal surgery (n=1) and VWD1 (n=2) during deliveries and surgery. Side effects observed in 16 patients were mainly minor, such as headache, facial flushing and tachycardia; water retention was reported in 2 cases (1 delivery, 1 surgery) only after >6 injections of the drug. Conclusions:Based on the results of this prospective clinical trial, we confirm that DDAVP is an effective and safe drug at low costs for managing patients with VWD1 and VWD2 once tested for their biological response: therefore it should be always considered as the first approach during bleedings and major/minor surgeries in responsive VWD patients. Disclosures:Federici:CSL Behring: Honoraria, Research Funding.

Genetic testing in von Willebrand disease: reply to rebuttal

See also Mannucci PM. Genetic testing in von Willebrand disease: a rebuttal. This issue, p 860.

The Anti Von Willebrand Factor Aptamer ARC1779 Prevents the Desmopressin-Induced Thrombocytopenia in VWD Type 2B.

Introduction: Von Willebrand Disease (VWD) Type 2B is characterized by increased affinity of VWF for the platelet glycoprotein receptor Ib (GPIb). Consequently, infusion of desmopressin, a standard of treatment for other forms of VWD, causes transient thrombocytopenia in patients with VWD-2B. The aim of the study was to test whether the novel anti-VWF aptamer ARC1779, which inhibits the interaction of VWF with GPIb, could abrogate the transient desmopressin-induced thrombocytopenia in VWD-2B.Patients and Methods: This was part of a clinical trial using a double-blind, randomized, placebo-controlled, crossover design. A patient with VWD 2B received desmopressin (0.4 mcg/kg) alone, or desmopressin after pre-treatment with ARC1779 targeted to a plasma concentration of 10 mcg/mL. Multiple blood samples were obtained over 24 hours to measure von Willebrand Factor Antigen, Ristocetin Cofactor (RiCO), FVIII activity and multimers.Results: Desmopressin alone (open circles) increased VWF:Ag by 38% (not shown), and VWF:RiCo 3.4-fold within 30 min, and profoundly decreased platelet counts by 87%. In striking contrast, ARC1779 (solid triangles) completely prevented the desmopressin induced fall in platelet counts (Figure), although the increase in vWF:Ag and vWF:RiCO was greater (2.7-fold and 12-fold, respectively).Conclusions: This randomized, double-blind, placebo-controlled experiment shows that ARC1779 effectively prevents consumption of VWF and platelets in response to desmopressin in VWD Type 2B. It provides in vivo proof of concept that ARC1779 is a potent inhibitor of the VWF A1 domain interaction with GPIb. [Display omitted]

The Role of Molecular Genetics in Diagnosing von Willebrand Disease

von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans, but its diagnosis, using conventional clinical criteria and phenotypic hemostasis test results, can be problematic. The von Willebrand factor gene was cloned in the mid-1980s, and since that time, a significant amount of information has been gathered with respect to the molecular pathology responsible for this trait. This accumulated information, along with advances in genetic technology, has now made the integration of molecular genetic testing for VWD a feasible option in some instances. In this review, we have summarized the current state of knowledge concerning the genetic causation of the various forms of VWD. We have also provided guidelines as to how genetic testing can be used to clarify diagnostic uncertainty that might remain after a clinical evaluation and routine coagulation testing has been completed.

Prophylaxis of bleeding episodes in patients with von Willebrand's disease.

Patients with severe forms of von Willebrand's disease (VWD) may have frequent haemarthroses, especially when factor VIII (FVIII) levels are below 10 U/dL, so that some of them develop target joints like patients with severe haemophilia A. Some patients have recurrent gastrointestinal bleeding, often without lesions in the gastrointestinal tract, and need treatment every day or every other day. Finally, there are children who have epistaxis frequently and severely enough to cause anaemia. In these frequent and severe bleeders, the optimal therapy may be secondary long-term prophylaxis with von Willebrand factor (VWF)/FVIII concentrates rather than on-demand treatment on the occasion of bleeding episodes. The largest experience on such prophylaxis in VWD has been in Sweden in 35 patients with severe forms of VWD. Long-term prophylaxis was also implemented in a cohort of Italian patients with VWD: prophylaxis was used in seven patients with types 3 (n = 1 ), 2A (n = 4), 2M (n = 1) and type 1 (n = 1) VWD because of recurrent gastrointestinal bleeds and in four patients with type 3 VWD because of joint bleeds. Prophylaxis prevented bleeding completely in eight patients and largely reduced hospitalisation for blood transfusions in the remaining three. The cost-effectiveness of these prophylaxis regimens versus on-demand therapy will now be investigated in one large international study

Surgical prophylaxis in von Willebrand's disease: a difficult balance to manage.

Von Willebrand disease (VWD) is the most common genetic bleeding disorder with a prevalence of approximately 1-2 percent confirmed in different population studies. The severity of the bleeding tendency is usually proportional to the degree of the VWF defect, although the large majority of cases diagnosed appear to have a mild disease. Patients with VWD may require short- or long-term prophylaxis treatment. Short-term prophylaxis is usually performed to prevent excessive bleeding following surgery or invasive procedures, while long-term prophylaxis may be needed to control recurrent mucosal and joint bleeding complicating the more severe forms of VWD. This review is focused on the current knowledge on replacement treatment for patients with VWD disease undergoing surgical or invasive procedures. On the whole, the published studies document the safety and efficacy of VWF/FVIII concentrates as surgical prophylaxis in VWD patients, in particular of Haemate P, the most widely used VWF/FVIII concentrate due to its high VWF:FVIII ratio. The recent literature data also show that the best management of VWD patients undergoing surgery is that to perform a pharmacokinetic study in order to strictly tailor for each VWD patient loading and maintenance doses of VWF/FVIII concentrates. Furthermore, the same studies underscore that, along with VWF levels, FVIII levels should be monitored in the peri-operative period in order to prevent exposures to high FVII levels, associated with an increased risk of venous thrombosis.

Acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AvWS) is a rare hemorrhagic diathesis with clinical symptoms similar to those associated with the inherited form of von Willebrand disease. This syndrome is characterized by the lack of previous bleeding symptoms, negative familial history, and occurrence in a relatively older age. Most commonly, AvWS develops in the course of other conditions such as lymphoproliferative, myeloproliferative, cardiovascular and autoimmune disorders; additionally it can be associated with some non-hematological malignancies and use of certain drugs. Pathogenesis of von Willebrand syndrome is complex and not fully understood. Deficiency or impaired activity of von Willebrand factor (vWF) can result from the presence of specific antibodies against this factor, its adsorption onto the surfaces of neoplastic cells, mechanic injury or proteolysis. Diagnosis is based on the measurements of plasma concentration and activity of vWF, and multimeric analysis. Management of AvWS includes the therapy of underlying disease and the control or prevention of bleeding. Hemostatic drugs

Acquired Factor VIII and von Willebrand Factor (aFVIII/VWF) Deficiency and Hypothyroidism in a Case With Hypopituitarism

This article reports a female who presented with bleeding, acquired factor VIII and von Willebrand factor (aFVIII-VWF) deficiency, and central deficiency in the thyroid and adrenal axis (Sheehan's syndrome). After starting hormone replacement therapy, relief of bleeding manifestations was associated with correction of both FVIII and VWF to normal. This report draws attention to a rare association between the acquired form of von Willebrand disease and hypothyroidism of central origin.